13-monomethyl cyclopentanopolyhydrophenantherenes and process



' M. REHRENsTl-:IN 2,530,816 ls-MoNoMEmL cYcLoPENTANoPoLyHYDRoPHENANTrmENEs N ov. 2l, 1950 AND PROCESS Filed Nov. 1e, 194e XO@ om v INVENTOR. Maximilian R ETenei-n ATTURNEYs Calculated for CzimoOi: C,72.78; Found: C,73.36, 72.78; H,8.30, 8.51.

Titration: 11.2 mg. of the product required 3.31 cc. ci (3.61 N NaOH; calculated iormonocarboxylic acid Cell-13004; 3.23 cc. l.

In this product as illustrated in the scheme the double bond has been indicated in the 5,6 position, though it may -be in the 5,10 position, or in the 4,5 position, or the product may be a mixture of any two or all of these isomers hereinafter indicated by reference to and/or isomers. However, no attempt was made to separate these isomers.

Proceeding now for the preparati-on of the compound D, which, for example, may be 3-acetoxylnoretiocholenic acid chloride (3-acetoxyestrene-l7-carboxylic acid chloride) and/or isomers, the compound C is directly transformed into the corresponding acid chloride and/or isomers by means of, for example, thionyl chloride, phosphorous oxychloride or phosphorous pentachloride. It will be understood that the compound D be prepared as an acid bromide by using an equivalent bromide in place of the aforementioned chlorides.

As exemplifying the procedure for the preparation of the compound D from the compound C, a purified, colorless thionyl chloride is prepared, for example, by distilling pure commercial thionyl chloride (Eastman), of a slightly yellow color, over quinoline and then over linseed oil. To 200 mg. of the compound C, and/or isomers, is added in a cold room 1.0 cc. of the purified thionyl chloride. The mixture is allowed to stand under anhydrous conditions in the cold room (about 2 C.) for a period of about 50 minutes and then at room temperature (20 C.) for about 3% hours, which usually results in the formation of an olive green solution. The solution thus formed is brought to dryness in vacuo (40 C.) under anhydrous conditions. The residue is then dried overnight in a vacuum dessicator (P2O5,KOH)

The acid chloride, or the bromide, thus prepared serves for the production of the compound E, as, for example, 3-acetoxy-lO-norpregnene- 20-one and/ or isomers.

The compound D, or related compounds indicated above and/or isomers, is of value not only as an intermediate for the preparation of the novel compound -norprogesterone according to the method of this invention, but likewise is useful for the preparation of the novel compound 10-nor-ll-desoxycorticosterone acetate, and which novel compound, together with various intermediates useful for its preparation and method for the preparation thereof, forms the subjectmatter of an application for patent filed by me perature (24 C.) for about 30 minutes.

4 Serial No. 147,970, led February 15, 1946, now Patent No. 2,496,450.

The preparation of the compound E, or related compounds indicated above and/or isomers, from the compound D is accomplished by treatment of the compound D or related compounds indicated above and/or isomers with a methylzinc halide, preferably methylzinc iodide or with dimethyl cadmium.

As exemplifying procedure for transforming, for example, the compound D to, for example, the compound E, a fuming, colorless solution of methylzinc iodide is prepared by adding a zinccopper couple, prepared from 2 g. of zinc (Zinc Reagent-Merck, Mossy cut in small pieces of 1-3 mm. size) and 0.2 g. of copper powder. by the method of Job and Reich, Bull. Soc. Chim. [4], 33, 1414 (1923), and an iodine crystal to a mixture of 2.33 g. of methyl iodide (Eastman, pure), 0.5 cc. of dry alcohol-free ethyl acetate, and 1.0 cc. of dry toluene. The mixture was heated (reux condenser) under anhydrous conditions in a metal bath to (C. Over a period of 11/2 hours the temperature was gradually raised to C., where it was kept for 45 minutes. After cooling to room temperature the mixture was diluted with 1.0 cc. of toluene.

The organo-zinc solution is decanted from excess metal and ice-cooled, then a solution of the compound D, prepared from 200 mg. of compound C, in 1.0 cc. of dry benzene is slowly added. The mixture is allowed to stand at room tem- After cooling with ice.` water is gradually added, which results in the formation of a thick precipitate which is brought into solution by adding an excess of N sulfuric acid until acid to Congo. The reaction mixture is then extracted with an ample quantity of ether and the ether extract washed with a concentrated solution of ammonium sulfate, water, a solution of N sodium hydroxide and then three times with small quantities of water (neutral ether extract).

The neutral ether extract is dried with sodium sulfate, brought to dryness in vacuo (40 C.) and the residue dried in a vacuum desiccator (P2Os; KOH). The residue is usually an orange-colored viscous oil, amounting to about mg.

The neutral residue is subjected to chromatographic adsorption by dissolving it in a mixture of 10 cc. of benzene and 25 cc. of petroleum ether and subsequently filtering through a column of 6.0 g. of aluminum oxide. The original solution is passed through within about two hours and the 4eluates each within 15 minutes. The following fractionation is obtained:

N o. of Weight of Frac- Solvent Residue, Appearance of Residue tlon mg.

10 cc: lenzene+25 cc. petr. ether 13.0 colorless sticky oil.

(original solution). 6 ce. benzene-H4 ce. petr. ether. 46. l slightly yellow sticky oil. 8 cc. benzene-H2 cc. petr. ether. 21.1 colorless resin. 10 cc. benzene-H0 ce. petr. ether 11.4 Do. 13 ce. benzene+7 cc. petr. ether- 6. 8 Do. 17 cc. benzene-+3 cc. petr. ether- 5. 9 Do. 20 cc. benzene 4. Do. 20 cc. benveue 2. 3 Do. 17 cc. benzene-t3 ce. ether 4. 2 Do. 13 ec. benzene-# 7 cc. ether-- 1. 9 Do. 10 cc. benzene-F10 cc. other. 1. 0 Do. 5 ce. benzene-H5 cc. ether.-- 0. 5 20 ce. ether 0.4 20 cc. ether 1. 1 colorless resin. 19 cc. ether-l-l ec. methanol- 6. 4 yellow resin. 16 80 ce. merhnnnl 10. 6 whitish-brownish residue.

Total i 137. 3

asso-,81e

Fractions 2-8, inclusive of the chromatogram (98.2 mg.) are combined and subjected to a distillation in high vacuum, heating to 110 C. within 10 minutes and gradual raising of the temperature to slightly above 200 C. within a period of one hour, which yields about 87.5 mg.

The major part oi the distillate (76.8 mg.) is subjected to further purification by means of Girards reagent T (betaine hydrazide hydrochloride) by the addition of 110 mg. of Girards reagent and 0.06 cc. of glacial acetic acid to the distillate dissolved in l1.0 cc. of methanol and reiiuxing on a water bath for 1 hour and then allowing to stand in the cold room for two days. Thereafter the mixture is cooled to 5 C. and about 1 g. of ice and an ice cold solution of 0.05 g. of sodium carbonate in l cc. of water is added. The mixture is then quickly extracted twice with ether in the cold room and the combined ether phases washed at room temperature successively with water, a solution of N sodium carbonateand four times with water. After drying with sodium sulfate and removal of the ether, an almost colorless resin is usually obtained (non-ketonic fraction).

tonic fraction) is usually obtained. An additional a amount of the ketonic fraction can be obtained by subjecting the non-ketonic fraction above to treatment with Girards reagent under the conditions indicated above.

The almost colorless, soft resin (ketonic fraction: about 47.4 mg.) obtained above is subjected to distillationin a high vacuum, yielding as the distillate usually a slightly yellow, viscous resin which comprises the compound E and/or lll) vwith water.

lbonate 'in' v0.5 cc. of water land 1 cc. of methanol.

The mixture is refluxed on a `Water bath'for V15d hours and is then made acid to Congo by the addition of dilute hydrochloric acid. The major part of the methanol is then removed in vacuo (40 C.) and the mixture extracted with ether. The ether phaseis washed with a little water, a solution of N sodium `carbonate 'and three times After drying with sodium sulfate and evaporation of the ether, usually an amber colored resin `comprising the compound F is Aobtained.

The preparation of l-norpro'gesterone (compound G) from the compound F and/oi` isomers is accomplished by dehydrogenation of the compound F using, for example, the method described by Oppenauer Rec. Trav. Chim. 56, 137 (1937), though other suitable methods for dehydrogenaticn maybe used.

As exemplifying procedure for transforming the compound F to the compound G, to 4 cc. of a clear solution of about 100 mg. of aluminum tert.butoxide (Eastman) in 1.0 cc.of dry benzene is added about 29.7 mg. of the compound .F dissolved in 1.2 cc. of dry acetone. The resulting solution is reiiu'xed under anhydrous conditions on a water bath for a period of 10 hou-rs, during Iwhich time an additional 0.2 cc. of -dry "acetone is added. The solution is permitted to stand at room temperature overnight, then an ample amount of ether and thereafter some N sulfuric acid are added to the solution. The ether phase is separated and washed with a-dilute-solution of sodium bicarbonate and three times with water. After drying with sodium sulfate and removal of the ether a yellowish, soft resin is usually obtained amounting to about 30.4 mg.

The resin thus obtained is purified by chromatographic adsorption by dissolving it in a mixture of 7.5 cc. of benzene and 22.5 cc. of petroleum ether and by subsequently filtering said solution through a column of 2.0 g. of aluminum oxide during a period of about three hours, the eluents being passed through each other a period of iS0me1-sle minutes. The following chromatographic frac- The preparation of the compound F, l0-nortionation 1s obtained:

N o. of Weight of A p earance of 7.5 cc.a benzene-P225 cc. petr. ether 1.9 colorless resin.

(original solution) 2.5 cc. benzene-F75 cc. petr. ether. 0. 6 colorless residue. 3.5 cc. benzene-$6.5 cc. petr. ethe1- 0. 2 Do. 5 ce. benzene-I- cc. pctr. ether..- i 1. 4 Do. 7 cc. benzene-Hi cc. peti". cthcr 4. 3 colorless resin. '9 cc. benzene-H ce. pctr. etlier. 4.1 Do. l0 cc. ben vene 2. 2 Do. l0 cc. bommie 0. 9 Do. 5s cc. bcnzcne-l-2 cc. ether 2. 4 colorless glass. 6 cc. benzene-H cc. ether 0. 6 colorless residue. 4 cc. benzene-Hi cc. ether l. 7 colorless resin. l0 cc. 'ether 2.1 o. l0 cc. ether Y 0. 2` Y Do. 7.5 cc. ether+2.5 cc. methanol 5. 4 light yellow glass. l0 ce. methanol 3. 0 whtisli mass.

Total 31. 0

pregnene-20-one,3ol, and/or isomers, from the compound E or related compounds indicated above and/or isomers, is accomplished by hydrolysis, preferably under alkaline conditions, of the compound E to replace the acyloxy group at carbon atom 3 with a hydroxyl group.

As exemplifying procedure for the hydrolysis of, for example, the compound E, 3-acetoxy-10- norpregnene-ZO-one and/or isomers, to 39.2 mg. of the compound E, dissolved in 1.0 cc. of methanol is added a solution of 0.1 g. of potassium car- The fractions 4-8, inclusive, of the above chromatogram are combined (about 12.9 mg.) and subjected to distillation in a high vacuum, heating to C. within about 10 minutes, and then gradually raising the temperature to slightly above 200 C. within a period of 40 minutes. The distillate, comprising l-norprogesterone, is usually an almost colorless (very pale yellow) soft resin which analyzes as follows:

Calculated for CzoHzaOz I C,79.94; H,9.40. Found: C,79.12; H,9.40.

The compound is further characterized by its ultra-violet absorption spectrum:

By reference to the scheme shown in the drawing it will be appreciated that from the broad standpoint this invention is not limited in the case of compounds D, E, F and G to compounds having the grouping COCl or COCI-Ia at carbon atom I'I, but to the contrary contemplates also broadly those compounds having the structure of compound D except for the fact that they have the grouping COX at carbon atom I'I, where X is chlorine or bromine, and also broadly those oompounds having the structure of compounds E, F and G except for the fact that they have the grouping COR at carbon atom II, where R is an alkyl group of not in excess of 10 carbon atoms, as for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, a phenyl group or a benzyl group. From the more specic standpoint, those compounds Where R is an alkyl group containing not more than ve carbon atoms are contemplated.

The compounds having the grouping COR at carbon atom II may be formed by treating the compound D to form the compound E as described above except for the use of an alkyl zinc halide of not in excess of l carbon atoms, a phenyl or a benzyl zinc halide or a dialkyl cadmium of not in excess of carbon atoms, a diphenyl or a dibenzyl cadmium in place of a methylzinc halide or dimethyl cadmium.

It will be understood, with reference to the several compounds above, that I do not intend that this invention or the claims appended hereto shall be limited to any particular conguration about any carbon atom and, in particular, about carbon atoms 3, I0, I4 and I1.

This application is a continuation-impart of an application led by me on March 24,1945, Serial No. 584,623, now abandoned.

What I claim and desire to protect by Letters Patent is:

1. A l3-monomethyl cyclopentanopolyhydrophenanthrene having the following structure:

C O R Where R is a member of the group consisting of alkyl groups of not in excess of ten carbon atoms.

illustrated and described 2. A compound according to claim l, characterized by the following structure:

i Il() 0 3 5 20 C O CH:

20 (IOOH o 17 oli-lg dehydrating and decarboxylating the acylation product by heating in vacuo, halogenating with a compound selected from the class consisting 01"' thionyl chloride, phosphorous oxychloride and phosphorous pentachloride, the product of dehydration and decarboxylation thereby effecting substitution of a member of the group consisting of chlorine and bromine for OH at carbon atom Eil, alkylating the halogenated product with an alkyl metal compound thereby effecting substitution of a member of the group consisting of alkyl of not in excess of ten carbon atoms for the halogen at carbon atom 8-, hydrolyzing the product of alkylation thereby effecting substitution of I-I for the acyl group at carbon atom 3 and dehydrogenating the product of hydrolysis at carbon atom 3.

MAXIMILIAN R. EHRENSTEIN.

REFERENCES CITED The following references are of record in the le of this patent:

UNITED STATES PATENTS Name Date Butenandt Feb. 18, 1941 Number 

1. A 13-MONOMETHYL - CYCLOPENTANOPOLYHYDROPHENANTHRENE HAVING THE FOLLOWING STRUCTURE: 